Concetta Alafaci

Beneficial effects of systemic administration of recombinant human erythropoietin in rabbits subjected to subarachnoid hemorrhage.

Cerebral vasospasm and ischemic damage are important causes of mortality and morbidity in patients affected by aneurysmal subarachnoid hemorrhage (SAH). Recently, i.p. administration of recombinant human erythropoietin (r-Hu-EPO) has been shown to exert a neuroprotective effect during experimental SAH. The present study was conducted to evaluate further the effect of r-Hu-EPO administration after SAH in rabbits on neurological outcome, degree of basilar artery spasm, and magnitude of neuronal ischemic damage. Experimental animals were divided into six groups: group 1 (n = 8), control; group 2 (n = 8), control plus placebo; group 3 (n = 8), control plus r-Hu-EPO; group 4 (n = 8), SAH; group 5 (n = 8), SAH plus placebo; group 6 (n = 8), SAH plus r-Hu-EPO. r-Hu-EPO, at a dose of 1,000 units/kg, and placebo were injected i.p. starting 5 min after inducing SAH and followed by clinical and pathological assessment 72 h later. Systemic administration of r-Hu-EPO produced significant increases in cerebrospinal fluid EPO concentrations (P < 0.001), and reduced vasoconstriction of the basilar artery (P < 0.05), ischemic neuronal damage (P < 0.001), and subsequent neurological deterioration (P < 0.05). These observations suggest that r-Hu-EPO may provide an effective treatment to reduce the post-SAH morbidity.

Effect of recombinant human erythropoietin on cerebral ischemia following experimental subarachnoid hemorrhage

Erythropoietin exerts a neuroprotective effect during cerebral ischemia. We investigated the effect of systemic administration of recombinant human erythropoietin in a rabbit model of subarachnoid hemorrhage-induced acute cerebral ischemia. The animals were divided into three groups: group 1, subarachnoid hemorrhage; group 2, subarachnoid hemorrhage plus placebo; group 3, subarachnoid hemorrhage plus recombinant human erythropoietin (each group, n=8). Experimental subarachnoid hemorrhage was produced by injecting autologous blood into the cisterna magna. Treatment with recombinant human erythropoietin and placebo was started 5 min after subarachnoid hemorrhage and was continued every 8 h for 24 h. Before the animals were killed, erythropoietin concentration was measured in the cerebrospinal fluid. The rabbits were killed 24 h after subarachnoid hemorrhage and ischemic brain injury was histologically evaluated. In group 3, the concentration of erythropoietin in the cerebrospinal fluid was significantly increased and a significant reduction in cortical necrotic neuron count was also observed. These findings may encourage the use of erythropoietin in the treatment of cerebral ischemia that often occurs in the early stage of subarachnoid hemorrhage.

Could nanoparticle systems have a role in the treatment of cerebral gliomas

UNLABELLED Malignant brain tumors are difficult to manage clinically and are associated with high rates of morbidity and mortality. Late diagnosis and the limitations of conventional therapies that may result from inefficient delivery of the therapeutic or contrast agent to brain tumors due to the blood-brain barrier and nonspecificity of the agents, are major reasons for this unsolved clinical problem. Nanotechnology involves the design, synthesis, and characterization of materials and devices that have a functional organization in at least one dimension on the nanometer scale. The nanoparticle has emerged as a potential vector for brain delivery, able to overcome the difficulties of modern strategies. Moreover, multifunctionality can be engineered into a single nanoplatform so that it can provide tumor-specific detection, treatment, and follow-up monitoring. This review reports the latest research in nanoparticle-based glioma treatment. FROM THE CLINICAL EDITOR In recent years, nanoparticles have emerged as potential delivery vectors targeting brain tumors, including multifunctional NP-s allowing tumor-specific detection, treatment, and follow-up monitoring. This review summarizes the latest research in nanoparticle-based glioma treatment.

Mutation Analysis of CCM1, CCM2 and CCM3 Genes in a Cohort of Italian Patients with Cerebral Cavernous Malformation

Cerebral cavernous malformations (CCMs) are vascular lesions of the CNS characterized by abnormally enlarged capillary cavities. CCMs can occur as sporadic or familial autosomal dominant form. Familial cases are associated with mutations in CCM1[K‐Rev interaction trapped 1 (KRIT1)], CCM2 (MGC4607) and CCM3 (PDCD10) genes. In this study, a three‐gene mutation screening was performed by direct exon sequencing, in a cohort of 95 Italian patients either sporadic or familial, as well as on their at‐risk relatives. Sixteen mutations in 16 unrelated CCM patients were identified, nine mutations are novel: c.413T > C; c.601C > T; c.846 + 2T > G; c.1254delA; c.1255‐4delGTA; c.1681‐1682delTA in CCM1; c.48A > G; c.82‐83insAG in CCM2; and c.396G > A in CCM3 genes. The samples, negative to direct exon sequencing, were investigated by MLPA to search for intragenic deletions or duplications. One deletion in CCM1 exon 18 was detected in a sporadic patient. Among familial cases 67% had a mutation in CCM1, 5.5% in CCM2, and 5.5% in CCM3, whereas in the remaining 22% no mutations were detected, suggesting the existence of either undetectable mutations or other CCM genes. This study represents the first extensive research program for a comprehensive molecular screening of the three known genes in an Italian cohort of CCM patients and their at‐risk relatives.

Bulbar Compression by an Ectatic Vertebral Artery: A Novel Neurovascular Construct Relieved by Microsurgical Decompression

OBJECTIVE: Brainstem compression caused by vascular abnormalities has rarely been reported in the literature. We describe five cases of large ectatic vertebral artery causing compression and distortion of the medulla oblongata with pyramidal tract signs and low cranial nerve dysfunction. Microvascular decompression by retracting the vertebral artery and anchoring it to the dura has been the treatment of choice. METHODS: Five patients, four male and one female, presented with progressive myelopathic features and lower cranial nerve dysfunction, especially dysphonia and dysphagia. Four patients were affected by systemic arterial hypertension. Magnetic resonance imaging showed impingement of the right vertebral artery in three patients and the left vertebral artery in two patients, on the right and left lateral medulla, respectively. In two patients, hypoplasia of the contralateral vertebral artery was documented. RESULTS: All patients underwent neurovascular decompression of the medulla oblongata. The ectatic and tortuous vertebral artery was detached from the medulla, shifted away, and repositioned by anchoring to the nearby dura mater using a Gore-Tex vascular slip. Postoperatively, all patients but one had improvement of their previous neurological symptoms. CONCLUSION: Brainstem dysfunction caused by a tortuous ectatic vertebral artery might be less uncommon than expected. It should be considered a new distinct clinical entity, the real incidence of which needs to be carefully evaluated by an appropriate diagnostic protocol, which includes primarily magnetic resonance imaging with specific three-dimensional sequences. Awareness of this condition is necessary to ensure the appropriate treatment. Surgical microvascular decompression seems very effective.

Assessment of human brain water content by cerebral bioelectrical impedance analysis: a new technique and its application to cerebral pathological conditions.

OBJECTIVE Total brain water content changes in several cerebral pathological conditions and the measurement of brain water content are important for the selection of appropriate therapeutic procedures. We present a quantitative, in vivo, bioelectrical impedance analysis (BIA) method and propose its use for the accurate assessment of brain water content among human subjects. METHODS Cerebral BIA is based on the conduction of an applied current in the brain parenchyma. Application of an excitatory current of 800 &mgr;A at 50 kHz, via two electrodes placed on the eyelids with the eyes closed, and detection of the voltage drop with two electrodes placed in the suboccipital region allow brain resistance and reactance to be measured. By means of an equation that considers cranial circumference and resistance, it is possible to quantify the total brain water content, expressed as the bioelectrical volume. Cerebral BIA was performed with a series of healthy volunteers (n = 100), for determination of average brain water content values. The method was then applied to 50 patients with brain tumors (n = 20), intracranial hemorrhage (n = 16), or hydrocephalus (n = 14), for assessment of changes in global brain water contents. Data were compared with those obtained for healthy volunteers. RESULTS Statistically significant differences (P < 0.001) were observed between the two groups. Mean brain water content values (expressed as bioelectrical volume values) were 38.2 ± 3.9 cm2/&OHgr; for healthy volunteers and 67.7 ± 13.1 cm2/&OHgr; for patients with cerebral pathological conditions. Statistically significant differences (P < 0.05) were also observed among patients with cerebral pathological conditions. CONCLUSION The results of this study suggest that BIA, applied to the cerebral parenchyma, is a valid method for the prediction of brain water contents under both normal and pathological conditions. However, further studies are needed to establish whether it is sensitive and reliable enough for future clinical applications.

Innovative Therapeutic Strategies in the Treatment of Brain Metastases

Brain metastases (BM) are the most common intracranial tumors and their incidence is increasing. Untreated brain metastases are associated with a poor prognosis and a poor performance status. Metastasis development involves the migration of a cancer cell from the bulk tumor into the surrounding tissue, extravasation from the blood into tissue elsewhere in the body, and formation of a secondary tumor. In the recent past, important results have been obtained in the management of patients affected by BM, using surgery, radiation therapy, or both. Conventional chemotherapies have generally produced disappointing results, possibly due to their limited ability to penetrate the blood–brain barrier. The advent of new technologies has led to the discovery of novel molecules and pathways that have better depicted the metastatic process. Targeted therapies such as bevacizumab, erlotinib, gefitinib, sunitinib and sorafenib, are all licensed and have demonstrated improved survival in patients with metastatic disease. In this review, we will report current data on targeted therapies. A brief review about brain metastatic process will be also presented.

MRI Tractography of Corticospinal Tract and Arcuate Fasciculus in High-Grade Gliomas Performed by Constrained Spherical Deconvolution: Qualitative and Quantitative Analysis

BACKGROUND AND PURPOSE: MR imaging tractography is increasingly used to perform noninvasive presurgical planning for brain gliomas. Recently, constrained spherical deconvolution tractography was shown to overcome several limitations of commonly used DTI tractography. The purpose of our study was to evaluate WM tract alterations of both the corticospinal tract and arcuate fasciculus in patients with high-grade gliomas, through qualitative and quantitative analysis of probabilistic constrained spherical deconvolution tractography, to perform reliable presurgical planning. MATERIALS AND METHODS: Twenty patients with frontoparietal high-grade gliomas were recruited and evaluated by using a 3T MR imaging scanner with both morphologic and diffusion sequences (60 diffusion directions). We performed probabilistic constrained spherical deconvolution tractography and tract quantification following diffusion tensor parameters: fractional anisotropy; mean diffusivity; linear, planar, and spherical coefficients. RESULTS: In all patients, we obtained tractographic reconstructions of the medial and lateral portions of the corticospinal tract and arcuate fasciculus, both on the glioma-affected and nonaffected sides of the brain. The affected lateral corticospinal tract and the arcuate fasciculus showed decreased fractional anisotropy (z = 2.51, n = 20, P = .006; z = 2.52, n = 20, P = .006) and linear coefficient (z = 2.51, n = 20, P = .006; z = 2.52, n = 20, P = .006) along with increased spherical coefficient (z = −2.51, n = 20, P = .006; z = −2.52, n = 20, P = .006). Mean diffusivity values were increased only in the lateral corticospinal tract (z = −2.53, n = 20, P = .006). CONCLUSIONS: In this study, we demonstrated that probabilistic constrained spherical deconvolution can provide essential qualitative and quantitative information in presurgical planning, which was not otherwise achievable with DTI. These findings can have important implications for the surgical approach and postoperative outcome in patients with glioma.

Integration of functional neuroimaging in CyberKnife radiosurgery: feasibility and dosimetric results

OBJECT The integration of state-of-the-art neuroimaging into treatment planning may increase the therapeutic potential of stereotactic radiosurgery. Functional neuroimaging, including functional MRI, navigated brain stimulation, and diffusion tensor imaging-based tractography, may guide the orientation of radiation beams to decrease the dose to critical cortical and subcortical areas. The authors describe their method of integrating functional neuroimaging technology into radiosurgical treatment planning using the CyberKnife radiosurgery system. METHODS The records of all patients who had undergone radiosurgery for brain lesions at the CyberKnife Center of the University of Messina, Italy, between July 2010 and July 2012 were analyzed. Among patients with brain lesions in critical areas, treatment planning with the integration of functional neuroimaging was performed in 25 patients. Morphological and functional imaging data sets were coregistered using the Multiplan dedicated treatment planning system. Treatment planning was initially based on morphological data; radiation dose distribution was then corrected in relation to the functionally relevant cortical and subcortical areas. The change in radiation dose distribution was then calculated. RESULTS The data sets could be easily and reliably integrated into the Cyberknife treatment planning. Using an inverse planning algorithm, the authors achieved an average 17% reduction in the radiation dose to functional areas. Further gain in terms of dose sparing compromised other important treatment parameters, including target coverage, conformality index, and number of monitor units. No neurological deficit due to radiation was recorded at the short-term follow-up. CONCLUSIONS Radiosurgery treatments rely on the quality of neuroimaging. The integration of functional data allows a reduction in radiation doses to functional organs at risk, including critical cortical areas, subcortical tracts, and vascular structures. The relative simplicity of integrating functional neuroimaging into radiosurgery warrants further research to implement, standardize, and identify the limits of this procedure.

Giant Olfactory Groove Meningiomas: Extent of Frontal Lobes Damage and Long-Term Outcome After the Pterional Approach

OBJECTIVE The treatment of giant olfactory groove meningiomas (OGMs; maximum diameter ≥ 6 cm) poses special problems and represents a surgical challenge. We discuss the long-term results in a series of 18 patients with giant OGMs and report our experience on a global strategy encompassing the pterional approach to manage the lesion and an extended transbasal approach to treat recurrences. METHODS Between February 1991 and December 2007, 18 patients with giant OGMs were surgically managed via a pterional craniotomy. Postoperative follow-up imaging was obtained at one, six, and 12 months and then yearly. In preoperative images, data from tumor volume were assessed. The volume of the residual right frontal porencephalic cave (ipsilateral to the operative side) was compared with the volume of the porencephalic cave measured in the left frontal lobe (internal control) in each case. Comparison between porencephalic cave and the original tumor volume for each side was also performed. RESULTS At the first operation in 17 of 18 patients (94.4%), the tumor resection was accomplished by a complete macroscopic lesion removal and coagulation of its dural attachment (Simpson grade II). In one patient, a Simpson grade V resection was obtained. The mean follow-up was 93.5 months, ranging from 12 to 214 months. Recurrences were observed in three patients (16.7%) at 103, 102, and 128 months, respectively, from the time of the first operation. These patients were operated on via an extended subfrontal transbasal approach accomplishing a complete (Simpson grade I) resection. No death occurred. The visual deficit improved in seven of 13 patients (53.8%), remained stable in five (38.5%), and worsened in one patient (7.7%). Overall, 17 of 18 patients (94.4%) had a good outcome and returned to their previous occupations. All the tumors presented with a symmetrical growth pattern. The mean meningioma volume was 23.51 ± 1.62 cm(3) for the right portion of the tumor and 23.04 ± 1.35 cm(3) for the left portion. The mean residual porencephalic volume was significantly smaller in the left frontal lobe (mean value 5.7 mL) than in the right frontal lobe (mean value 16.6 mL; P < 0.05). The mean residual porencephalic volume was significantly smaller than the tumor volume both in the left (P < 0.01) and in the right side (P < 0.05). CONCLUSION The pterional-transsylvian approach provides two major advantages: first, it minimizes morbidity and mortality through an early neurovascular control and by limiting parenchymal damage as demonstrated by a quantitative analysis; second it is associated with low recurrence rate at a long-term follow-up.